T cell homeostasis and tolerance are governed by proper orchestration of multiple factors expressed on T cells, including antigen receptors, costimulatory molecules and inhibitory molecules. In addition, T cell tolerance is controlled via cell-cell interactions with antigen presenting cells of a certain status (e.g., immature or mature dendritic cells) or by regulatory T cells. The major goal of this proposal is to understand how T cell tolerance or fate is controlled, in particular, via cell-intrinsic means. This application stems from our preliminary data on the role of the signaling adapter TRAF6 in T cells. Our preliminary data, generated from TRAF6 conditional knockout mice crossed to CD4-cre transgenic mice (TRAF6-deltaT), show that when TRAF6 is deleted in T cells mice develop splenomegaly and lymphadenopathy associated with T cell hyperproliferation. These results imply that (i) TRAF6 has a previously unrecognized, cell-intrinsic role in T lymphocytes, and (ii) TRAF6 may act as a "negative" regulator of T cell homeostasis. These results are quite unexpected since immunoreceptors utilizing TRAF6, such as CD40 or IL-1/Toll-like receptors (TLRs), are mostly implicated in the regulation of ARC function. Hence, we propose to extend the study of T cell biology, as regulated by TRAF6, by pursuing the following aims: (i) to determine cellular defects leading to the lymphoproliferative disease observed in TRAF6-deltaT mice, (ii) to determine molecular defects of T cells lacking TRAF6, and (iii) to utilize TRAF6-deltaT mice possessing defined antigen specificity to determine how TRAF6 regulates T cells during maturation and activation, and how this relates to the defect in immune homeostasis. The proposed studies should define a previously unrecognized mechanism(s) for how T cell tolerance and fate are controlled at the molecular and cellular level. Such studies will provide the basis for novel intervention strategies against various autoimmune diseases and for new methods to enhance T cell immune responses against cancer.